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Dipyridamole in the treatment of angina pectoris: A meta-analysis
THROMBOSIS RESEARCH Supplement XII; 35;42,1990 004~3949/90 $3.00 + .OO Printed In the USA. Cowright (c) 1990 Pergamon Press pk. All rights reserved.
DIPYRIDAMOLE
JN THE TREATMENT OF ANGINA PECTORIS: A META-ANALYSIS
H.S. Sacks, J. Berrier, R. Nagalingham and T.C. Chalmers Mount Sinai Medical Center, New York, NY, USA ABSTRACT A meta-analysis of 11 randomized trials published between 1960 and 1970 was performed to re-evaluate data on the efficacy of dipyridamole in the prevention and treatment of chronic angina pectoris. Three trials significantly favored drug vs placebo, four showed a trend towards drug us placebo, two showed no difference and two showed a trend towards placebo usdrug. The combined results of these 11 trials showed a statistically significant improvement with dipyridamole. Although this result should be viewed with caution because of methodologic variations in the studies, the available evidence appears to suggest that dipyridamole may have a beneficial effect, and that it may have been prematurely discarded in the treatment of angina pectoris.
lNTRODUCTION Dipyridamole has been studied extensively in disease states in which its vascular effects were thought to be potentially beneficial, for example, coronary artery disease, myocardial infarction, cerebrovascular disease and prosthetic heart valve replacement. Recent interest in dipyridamole has focused on its effects as an antiplatelet agent and on its role as an adjunct to aspirin in the prevention of stroke and myocardial infarction (1). A number of poorly-controlled studies and several double-blind, placebo-controlled trials on the prevention of angina pectoris have been carried out for dipyridamole, but with inconsistent results. Due to the variety of study results, many authorities concluded that the benefit of dipyridamole in angina pectoris was not proven, and thus the drug did not become widely accepted for the treatment of this disease. We have re-evaluated the data on dipyridamole in the treatment of chronic or stable angina using the method of meta-analysis (2). Meta-analysis is the systematic analysis of data gathered from multiple research projects. When applied to clinical trials, it is the process of evaluating the quality, and statistically combining the results of more than one trial. Meta-analysis is useful in resolving uncertainty when reports disagree, in overcoming sample size deficiencies and in improving effect size estimates. It is particularly applicable to randomized control trials (RCTs) as such trials are often too small to detect clinically important differences. Synonyms for meta-analysis include ‘quantitative synthesis’, ‘quantitative reviewing ‘, ‘summary studies’, ‘evaluation research’ and, somewhat more vaguely, ‘overview’. Key words: meta-analysis, dipyridamole, angina pectoris, Persantine, not animal.
35
36
DIPYRIDAMOLE:
A META-ANALYSIS
Suppl. XII, 1990
METHODS AND DATA Princioles for meta-analvsis Meta-analysis should be planned prospectively, with a written protocol for the research plan detailing the aims of the study, the criteria for trial inclusion and the methods to be used. Blinding as to the source and results of included trials is maintained, as knowledge of the investigators, place or date of the trial might admit bias with regard to the adequacy of the study. Finally, each study is reviewed and data extracted in duplicate by two independent reviewers, and inter-observer agreement should be secured. Literature search The literature search covered the period from the 1960’s through to December 1989 indexing the key-words ‘dipyridamole’, ‘Persantine’, ‘angina pectoris’ and ‘not animal’. We found 31 articles reporting clinical trials of dipyridamole in the treatment or prophylaxis of chronic or stable angina. Only ten of these studies, however, fulfilled all our criteria: patients were allocated randomly to treatment and control groups, dipyridamole was compared to placebo only and the reported data were adequate for analysis. One of the articles reported both a low-dose and a high-dose trial compared to the same placebo group. These trials were counted separately, making a total of 11 RCTs to be included in our analysis. These trials were all published between I960 and 1970. Trial data Of the 11 trials, 7 were crossover and 4 were non-crossover. Details of the studies included are given in Table 1. The dose of dipyridamole ranged from 37.5-200 mg/day, and the duration of treatment from 2 weeks to 7 months. The number of patients in each trial ranged from 10 to 56. Statistical analvsis The results of these 11 trials were combined by two different meta-analytical methods. The of information from data modified Mantel-Haenszel method (14) allows the combination tabulated in a 2 row by 2 column format (treated/control vsimptoved/not improved), yielding an odds ratio of improvement in the control group compared to treatment. The method of DerSimonian and Laird (15) uses a random effects approach, allowing for the heterogeneity of effects in the overall treatment efficacy. Results of this analysis are expressed as an adjusted mean difference, or treatment effect. Zero treatment effect means no difference, and a statistically significant effect has a 95% confidence interval that does not include zero. Two sets of calculations were made. First, the numbers of patients who were reported, in each article, as improved when taking either dipyridamole or placebo were compared. Secondly, all patients dropped from a trial for whatever reason (including death) were allocated to the dipyridamole arm, unless specifically stated otherwise in the article. This was a ‘worst-case’ scenario and included patients who had been excluded from published results. ORIGINAL TRIAL RESULTS Referring to Table 1, the trials by Zion and Kinsella showed equal efficacies of dipyridamole and placebo (p = 1 .O>. The small sample sizes and improvement percentages should be noted. Of the remaining five crossover studies, only one showed a statistically significant improvement with dipyridamole. In the four non-crossover studies, though more patients improved in each study on
9 10 11 12
3 4
Reference number
25
225
17123 22/28 21/26 8/14
6 7 2-7
9119 5/17 13/20 14/24
l/5 O/8
5/14
Patient number
3+ 0.5 1.5 1
0.5 0.5 1
Duration (months)
150 150 200
150 200
37.5 37.5 100 100 100
(m$
Daily dosage
57
79 81
74
29 65 58
36 20 0 47
%
Dipyridamole improved Placebo improved
15/24 O/28 2/22 4/13
l/5 l/8 2/19 7/17 7/16 11/24
5/14
Patient number
TABLE 1 RCTs Included in the Meta-Analysis
Reproduced, with permission, from Sacks. H.S. et al. (13).
Sbar (1967) Wirecki (1967) Igloe (1970) Becker (1967)
Leiberman (1964) Dewar (1961) Neumann (1964) Foulds (1960) No-crossover
Crossover Zion (1961) Kinsella (1962)
First author (date)
Dipyridamole
9 31
62 0
36 20 12.5 10.5 41 44 46
%
bO.400.20
1.0 1.0 >0.30 <0.02 >0.40 >0.20 BO.30
p value
38
DIPYRIDAMOLE:
Suppl. XII, 1990
A META-ANALYSIS
dipyridamole, only two gave significant results favoring the drug. The doses of dipyridamole used in these four trials were generally higher (150-225 mg/day) than in the crossover studies, and the study duration was longer (2-7 months). The adequacy of these trials with respect to our quality scoring system (16) is shown in Table 2. All these trials scored high on blinding criteria, as this was essential for inclusion in our study. On the whole, data presentation was poor, particularly in the area of accounting for the fate of all patients. Only five papers gave numbers and reasons for patients withdrawn after randomization, none analyzed withdrawals in more than one way and none gave a statistical estimate of the sample size needed to show an effect. The performance and reporting of statistical analysis was also poor. None of the studies reported attack frequency related to time, none reported confidence limits and only 3 reported both test statistics and p values. TABLE 2 RCT Adequacy for Meta-Analysis
Essential. quality items
Number of adequate trials
Blinding of: treatment assignment patients to therapy physicians/observers to therapy physicians/observers to ongoing results Data presentation Numbers and reasons for patients excluded before randomization Statistical estimate of sample size Numbers and reasons for patients withdrawn after randomization Withdrawals analyzed several ways Statistical analyses Both test statistics and p values given Life tables or repeated measures given when appropriate 95% confidence intervals or SEMs given
7 10 9 4 0 0
5 0
3 0 0
Reproduced, with permission, from Sacks, H.S. et al. (13).
hfETA-ANALYSIS RESULTS Odds ratios The odds ratios for each trial and the combined data, calculated by the modified MantelHaenszel method, are shown in Figure 1. The odds ratio represents the odds of improvement on placebo compared with dipyridamole treatment. The vertical line represents an odds ratio
DIPYRIDAMOLE:
Suppl. XII, 1990
Mantel-Haenszel
A META-ANALYSIS
39
FIGURE 1 Analysis of the 11 Separate RCTs and of the Combined
Data.
Favors control Becker Igloe Sbar Zion Dewar Kinsella Wirecki
-I--
Foulds
c/
Leiberman Reumann Combined
I.4
I/
I
I,
Odds ratio Individual
trials are identified
0
1
by first author,
2
3
and combined
4
5
6
7
results are also shown.
“19 Bars represent 95%
confidence intervals of the calculated odds ratios. Reproduced, with permission, from Sacks el al. (13).
of one, that is, no difference between placebo and dipyridamole in terms of symptom relief. The trials which showed a statistically significant effect of dipyridamole on original analysis all exhibit odds ratios of less than 1 with narrow confidence intervals which do not include 1. The odds ratios of the individual trials varies from 0.04 (highly significant) to 1.65 (possibly harmful, but not significantly so>. The combined data yield an odds ratio of 0.29, with a 95% confidence interval of 0.19-0.43. The DerSimonian and Laird method gave a mean treatment effect of 0.24 (& 0.11 SEM) with a 95% confidence interval of 0.02-0.46. This was a statistically significant effect favouring dipyridamole ( p < 0.05). ‘Worst-case’ analvsis This comparison allocated all patients withdrawn for whatever reason (including death), to the dipyridamole group, unless specifically stated otherwise in the article. Using the modified Mantel-Haenszel method of data combination, a significant effect of dipyridamole was shown, (odds ratio 0.34 with a 95% confidence interval of 0.25-0.50). The DerSimonian and Laird method gave a treatment effect of 0.21(* 0.12 SEM) with 95% confidence limits of -0.02-0.44. This was not significant at the 5% level ( p = 0.07).
40
DIPYRIDAMOLE: A META-ANALYSIS
Suppl. XII, 1990
We have re-examined data on the question of the efficacy of dipyridamole in the prevention Meta-analysis of this data from 11 RCTs has shown a and treatment of angina pectoris. statistically significant improvement with dipyridamole. There are several methodological pitfalls, however, which need to be discussed. First, was the pooling of the results of these 11 separate trials appropriate? Due to various factors, including the combination of crossover with non-crossover studies, a Chi-square test of homogeneity revealed a high degree of between-study variability Cx’= 62,p < 0.005). There was also a great deal of clinical variation in terms of, for example, patient characteristics, drug dosage and treatment duration. This variation was partially countered by several different methods of statistical analysis, including one method specifically designed to incorporate an allowance for heterogeneity. Both statistical methods gave a significant result favouring dipyridamole. Careful attention to the blinding process is essential in evaluating therapies for a disease like angina pectoris where the end-points are subjective. Only one of the papers we reevaluated (5) reported testing of the blinding process by asking physicians which patients they thought had received placebo or dipyridamole. The physicians were consistently correct, suggesting that either the drug was markedly effective, or the blinding process was flawed. No other studies checked the blinding process. In many of the articles, the number of patients in the final report was lower than the number initially recruited into the trial. This is in contravention of the currently accepted RCT procedure of ‘intention to treat’ analysis, where all patients in a group are assessed regardless of how much assigned therapy they received. In several instances, where patients who died during the study were excluded from analysis, a biased impression of the efficacy of dipyridamole could be achieved. A not insignificant factor in the data available for meta-analysis is publication bias. Often, studies showing a statistically significant beneficial effect are more likely to be published than those that do not. In the present study, however, more trials showed non-beneficial effects, suggesting that this particular bias was not a problem in this case. A method is available for calculating the number of unpublished negative studies required to invalidate a meta-analysis (17). The number of unpublished negative results required to invalidate the present analysis is an unlikely 85. Dipyridamole has been shown to precipitate angina1 symptoms when given intravenously to patients with coronary artery disease (4, 18, 19). Also, patients enrolled in the Persantin-Aspirin Reinfarction Study (20) who received dipyridamole with aspirin showed a not statistically significant trend towards angina onset compared with placebo-treated subjects (20). We stress that our results should be interpreted with these data in mind. In conclusion, the available evidence, when re-evaluated, suggests that dipyridamole may have a beneficial effect in angina pectoris and may have been prematurely discarded. However, the methodological problems in the original studies suggest that the results of this meta-analysis should be viewed cautiously. Further, carefully designed studies should be performed to determine the true efficacy of dipyridamole in the treatment of this disease.
1
FITZGERALD, G.A. Dipyridamole.
NEngl JMed, 326, 1247-1257,
1987.
Suppl. XII, 1990
DIPYRIDAMOLE:
A META-ANALYSIS
41
2 SACKS, H.S., BERRIER, J., REITMAN, D., ANCONA-BERK, V.A. and CHALMERS, T.C. Meta-analyses of randomized controlled trials. N Engl JMed, 316, 450-455, 1987. 3 ZION, M.M. and BRADLOW, B.A. A controlled pectoris. South AfrMedJ, 35, 11-13, 1961.
clinical trial of “persantin”
@AS) in angina
4 KINSELLA, D., TROUP, W. and MCGREGOR, M. Studies with a new coronary vasodilator Am HeatiJ, 63, 146-151, 1962. drug: Persantin. 5
LEIBERMAN, A. and GUGLIELMELLI, S. Persantin - a double blind study. Angiology, 15,
290-292, 1964. 6 DEWAR, H.A.and HORLER, A.R. A clinical trial of persantin of angina of effort. Scott MedJ, G, 149-152, 1961.
and crodimyl in the treatment
7 NEUMANN, M. and LUISADA, A.A. Effect of rapid and slow-acting precordial pain of the aged. Am JMed Sci, 247, 156-163, 1964. 8
FOULDS, T. and MACKINNON, J. Controlled double-blind of angina pectoris. Br MedJ5202, 835, 1960. 9 SBAR, S. and SCHLANT, R.C. Dipyridamole in the treatment blind evaluation. JAMA, 201, 865-867, 1967.
trial of “persantin”
of angina
in treatment
of angina pectoris: a double-
10 WIRECKI, M. Treatment of angina pectoris with dipyridamole: study. J&-on Dis, 20, 139-145, 1967. 11 IGLOE, M.C. Treatment
“coronary” drugs on
pectoris with dipyridamole:
a long-term
double-blind
a double-blind
study.
J
Am Geriat Sot, 18, 233-241, 1970. 12 BECKER, M.C. Angina pectoris: a double-blind
study with dipyridamole.
JNeuark Beth
Israel Hasp, 18, 88-94, 1967. 13 SACKS, H.S., ANCONA-BERK, V.A., BERRIER, J.,NAGALINGHAM, R. and CHALMERS, T.C. Dipyridamole in the treatment of angina pectoris: A meta-analysis. Clin Pharmacol7ber, 43,610-615, 1988. 14 YUSUF, S., PETO, R., LEWIS, J., COLLINS, R. and SLEIGHT, P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis, 27, 335-371, 1985. 15 DERSIMONIAN, R. and LAIRD, N. Meta-analysis
in clinical trials.
Controlled Clin Trials,
7, 177-188, 1986. 16 CHALMERS, T.C., SMITH, H.JR, BLACKBURN, B., SILVERMAN, B., SCHROEDER. B., REITMAN, D. and AMBROZ, A. A method for assessing the quality of a randomized control trial. Controlled Clin Trials, 2, 231-249, 1981.
42
DIPYRIDAMOLE:
Suppl. XII, 1990
A META-ANALYSIS
17 ROSENTHAL, R. The “file drawer problem” 86, 638-641, 1979.
and tolerance
for null results.
Psycbol Bull,
18 WILCKEN, D.E.L., PAOLONI, H.J. and EIKENS, E. Evidence for intravenous dipyridamole (Persantin) producing a “coronary steal” effect in the ischaemic myocardium. Ausf NZJMed, I, 8-14, 1971. 19 FELDMAN, R.L., NICHOLS, W.W., PEPINE, C.J. and CONTI, C.R. Acute effect of intravenous dipyridamole on regional coronary hemodynamics and metabolism. Circulation, 64,333344, 1981. 20 The Persantine-Aspirin Reinfarction Study Research Group. coronary heart disease. Circulation, 62, 449-461, 1980.
Persantine
and aspirin in
DIPYRIDAMOLE
JN THE TREATMENT OF ANGINA PECTORIS: A META-ANALYSIS
H.S. Sacks, J. Berrier, R. Nagalingham and T.C. Chalmers Mount Sinai Medical Center, New York, NY, USA ABSTRACT A meta-analysis of 11 randomized trials published between 1960 and 1970 was performed to re-evaluate data on the efficacy of dipyridamole in the prevention and treatment of chronic angina pectoris. Three trials significantly favored drug vs placebo, four showed a trend towards drug us placebo, two showed no difference and two showed a trend towards placebo usdrug. The combined results of these 11 trials showed a statistically significant improvement with dipyridamole. Although this result should be viewed with caution because of methodologic variations in the studies, the available evidence appears to suggest that dipyridamole may have a beneficial effect, and that it may have been prematurely discarded in the treatment of angina pectoris.
lNTRODUCTION Dipyridamole has been studied extensively in disease states in which its vascular effects were thought to be potentially beneficial, for example, coronary artery disease, myocardial infarction, cerebrovascular disease and prosthetic heart valve replacement. Recent interest in dipyridamole has focused on its effects as an antiplatelet agent and on its role as an adjunct to aspirin in the prevention of stroke and myocardial infarction (1). A number of poorly-controlled studies and several double-blind, placebo-controlled trials on the prevention of angina pectoris have been carried out for dipyridamole, but with inconsistent results. Due to the variety of study results, many authorities concluded that the benefit of dipyridamole in angina pectoris was not proven, and thus the drug did not become widely accepted for the treatment of this disease. We have re-evaluated the data on dipyridamole in the treatment of chronic or stable angina using the method of meta-analysis (2). Meta-analysis is the systematic analysis of data gathered from multiple research projects. When applied to clinical trials, it is the process of evaluating the quality, and statistically combining the results of more than one trial. Meta-analysis is useful in resolving uncertainty when reports disagree, in overcoming sample size deficiencies and in improving effect size estimates. It is particularly applicable to randomized control trials (RCTs) as such trials are often too small to detect clinically important differences. Synonyms for meta-analysis include ‘quantitative synthesis’, ‘quantitative reviewing ‘, ‘summary studies’, ‘evaluation research’ and, somewhat more vaguely, ‘overview’. Key words: meta-analysis, dipyridamole, angina pectoris, Persantine, not animal.
35
36
DIPYRIDAMOLE:
A META-ANALYSIS
Suppl. XII, 1990
METHODS AND DATA Princioles for meta-analvsis Meta-analysis should be planned prospectively, with a written protocol for the research plan detailing the aims of the study, the criteria for trial inclusion and the methods to be used. Blinding as to the source and results of included trials is maintained, as knowledge of the investigators, place or date of the trial might admit bias with regard to the adequacy of the study. Finally, each study is reviewed and data extracted in duplicate by two independent reviewers, and inter-observer agreement should be secured. Literature search The literature search covered the period from the 1960’s through to December 1989 indexing the key-words ‘dipyridamole’, ‘Persantine’, ‘angina pectoris’ and ‘not animal’. We found 31 articles reporting clinical trials of dipyridamole in the treatment or prophylaxis of chronic or stable angina. Only ten of these studies, however, fulfilled all our criteria: patients were allocated randomly to treatment and control groups, dipyridamole was compared to placebo only and the reported data were adequate for analysis. One of the articles reported both a low-dose and a high-dose trial compared to the same placebo group. These trials were counted separately, making a total of 11 RCTs to be included in our analysis. These trials were all published between I960 and 1970. Trial data Of the 11 trials, 7 were crossover and 4 were non-crossover. Details of the studies included are given in Table 1. The dose of dipyridamole ranged from 37.5-200 mg/day, and the duration of treatment from 2 weeks to 7 months. The number of patients in each trial ranged from 10 to 56. Statistical analvsis The results of these 11 trials were combined by two different meta-analytical methods. The of information from data modified Mantel-Haenszel method (14) allows the combination tabulated in a 2 row by 2 column format (treated/control vsimptoved/not improved), yielding an odds ratio of improvement in the control group compared to treatment. The method of DerSimonian and Laird (15) uses a random effects approach, allowing for the heterogeneity of effects in the overall treatment efficacy. Results of this analysis are expressed as an adjusted mean difference, or treatment effect. Zero treatment effect means no difference, and a statistically significant effect has a 95% confidence interval that does not include zero. Two sets of calculations were made. First, the numbers of patients who were reported, in each article, as improved when taking either dipyridamole or placebo were compared. Secondly, all patients dropped from a trial for whatever reason (including death) were allocated to the dipyridamole arm, unless specifically stated otherwise in the article. This was a ‘worst-case’ scenario and included patients who had been excluded from published results. ORIGINAL TRIAL RESULTS Referring to Table 1, the trials by Zion and Kinsella showed equal efficacies of dipyridamole and placebo (p = 1 .O>. The small sample sizes and improvement percentages should be noted. Of the remaining five crossover studies, only one showed a statistically significant improvement with dipyridamole. In the four non-crossover studies, though more patients improved in each study on
9 10 11 12
3 4
Reference number
25
225
17123 22/28 21/26 8/14
6 7 2-7
9119 5/17 13/20 14/24
l/5 O/8
5/14
Patient number
3+ 0.5 1.5 1
0.5 0.5 1
Duration (months)
150 150 200
150 200
37.5 37.5 100 100 100
(m$
Daily dosage
57
79 81
74
29 65 58
36 20 0 47
%
Dipyridamole improved Placebo improved
15/24 O/28 2/22 4/13
l/5 l/8 2/19 7/17 7/16 11/24
5/14
Patient number
TABLE 1 RCTs Included in the Meta-Analysis
Reproduced, with permission, from Sacks. H.S. et al. (13).
Sbar (1967) Wirecki (1967) Igloe (1970) Becker (1967)
Leiberman (1964) Dewar (1961) Neumann (1964) Foulds (1960) No-crossover
Crossover Zion (1961) Kinsella (1962)
First author (date)
Dipyridamole
9 31
62 0
36 20 12.5 10.5 41 44 46
%
bO.40
1.0 1.0 >0.30 <0.02 >0.40 >0.20 BO.30
p value
38
DIPYRIDAMOLE:
Suppl. XII, 1990
A META-ANALYSIS
dipyridamole, only two gave significant results favoring the drug. The doses of dipyridamole used in these four trials were generally higher (150-225 mg/day) than in the crossover studies, and the study duration was longer (2-7 months). The adequacy of these trials with respect to our quality scoring system (16) is shown in Table 2. All these trials scored high on blinding criteria, as this was essential for inclusion in our study. On the whole, data presentation was poor, particularly in the area of accounting for the fate of all patients. Only five papers gave numbers and reasons for patients withdrawn after randomization, none analyzed withdrawals in more than one way and none gave a statistical estimate of the sample size needed to show an effect. The performance and reporting of statistical analysis was also poor. None of the studies reported attack frequency related to time, none reported confidence limits and only 3 reported both test statistics and p values. TABLE 2 RCT Adequacy for Meta-Analysis
Essential. quality items
Number of adequate trials
Blinding of: treatment assignment patients to therapy physicians/observers to therapy physicians/observers to ongoing results Data presentation Numbers and reasons for patients excluded before randomization Statistical estimate of sample size Numbers and reasons for patients withdrawn after randomization Withdrawals analyzed several ways Statistical analyses Both test statistics and p values given Life tables or repeated measures given when appropriate 95% confidence intervals or SEMs given
7 10 9 4 0 0
5 0
3 0 0
Reproduced, with permission, from Sacks, H.S. et al. (13).
hfETA-ANALYSIS RESULTS Odds ratios The odds ratios for each trial and the combined data, calculated by the modified MantelHaenszel method, are shown in Figure 1. The odds ratio represents the odds of improvement on placebo compared with dipyridamole treatment. The vertical line represents an odds ratio
DIPYRIDAMOLE:
Suppl. XII, 1990
Mantel-Haenszel
A META-ANALYSIS
39
FIGURE 1 Analysis of the 11 Separate RCTs and of the Combined
Data.
Favors control Becker Igloe Sbar Zion Dewar Kinsella Wirecki
-I--
Foulds
c/
Leiberman Reumann Combined
I.4
I/
I
I,
Odds ratio Individual
trials are identified
0
1
by first author,
2
3
and combined
4
5
6
7
results are also shown.
“19 Bars represent 95%
confidence intervals of the calculated odds ratios. Reproduced, with permission, from Sacks el al. (13).
of one, that is, no difference between placebo and dipyridamole in terms of symptom relief. The trials which showed a statistically significant effect of dipyridamole on original analysis all exhibit odds ratios of less than 1 with narrow confidence intervals which do not include 1. The odds ratios of the individual trials varies from 0.04 (highly significant) to 1.65 (possibly harmful, but not significantly so>. The combined data yield an odds ratio of 0.29, with a 95% confidence interval of 0.19-0.43. The DerSimonian and Laird method gave a mean treatment effect of 0.24 (& 0.11 SEM) with a 95% confidence interval of 0.02-0.46. This was a statistically significant effect favouring dipyridamole ( p < 0.05). ‘Worst-case’ analvsis This comparison allocated all patients withdrawn for whatever reason (including death), to the dipyridamole group, unless specifically stated otherwise in the article. Using the modified Mantel-Haenszel method of data combination, a significant effect of dipyridamole was shown, (odds ratio 0.34 with a 95% confidence interval of 0.25-0.50). The DerSimonian and Laird method gave a treatment effect of 0.21(* 0.12 SEM) with 95% confidence limits of -0.02-0.44. This was not significant at the 5% level ( p = 0.07).
40
DIPYRIDAMOLE: A META-ANALYSIS
Suppl. XII, 1990
We have re-examined data on the question of the efficacy of dipyridamole in the prevention Meta-analysis of this data from 11 RCTs has shown a and treatment of angina pectoris. statistically significant improvement with dipyridamole. There are several methodological pitfalls, however, which need to be discussed. First, was the pooling of the results of these 11 separate trials appropriate? Due to various factors, including the combination of crossover with non-crossover studies, a Chi-square test of homogeneity revealed a high degree of between-study variability Cx’= 62,p < 0.005). There was also a great deal of clinical variation in terms of, for example, patient characteristics, drug dosage and treatment duration. This variation was partially countered by several different methods of statistical analysis, including one method specifically designed to incorporate an allowance for heterogeneity. Both statistical methods gave a significant result favouring dipyridamole. Careful attention to the blinding process is essential in evaluating therapies for a disease like angina pectoris where the end-points are subjective. Only one of the papers we reevaluated (5) reported testing of the blinding process by asking physicians which patients they thought had received placebo or dipyridamole. The physicians were consistently correct, suggesting that either the drug was markedly effective, or the blinding process was flawed. No other studies checked the blinding process. In many of the articles, the number of patients in the final report was lower than the number initially recruited into the trial. This is in contravention of the currently accepted RCT procedure of ‘intention to treat’ analysis, where all patients in a group are assessed regardless of how much assigned therapy they received. In several instances, where patients who died during the study were excluded from analysis, a biased impression of the efficacy of dipyridamole could be achieved. A not insignificant factor in the data available for meta-analysis is publication bias. Often, studies showing a statistically significant beneficial effect are more likely to be published than those that do not. In the present study, however, more trials showed non-beneficial effects, suggesting that this particular bias was not a problem in this case. A method is available for calculating the number of unpublished negative studies required to invalidate a meta-analysis (17). The number of unpublished negative results required to invalidate the present analysis is an unlikely 85. Dipyridamole has been shown to precipitate angina1 symptoms when given intravenously to patients with coronary artery disease (4, 18, 19). Also, patients enrolled in the Persantin-Aspirin Reinfarction Study (20) who received dipyridamole with aspirin showed a not statistically significant trend towards angina onset compared with placebo-treated subjects (20). We stress that our results should be interpreted with these data in mind. In conclusion, the available evidence, when re-evaluated, suggests that dipyridamole may have a beneficial effect in angina pectoris and may have been prematurely discarded. However, the methodological problems in the original studies suggest that the results of this meta-analysis should be viewed cautiously. Further, carefully designed studies should be performed to determine the true efficacy of dipyridamole in the treatment of this disease.
1
FITZGERALD, G.A. Dipyridamole.
NEngl JMed, 326, 1247-1257,
1987.
Suppl. XII, 1990
DIPYRIDAMOLE:
A META-ANALYSIS
41
2 SACKS, H.S., BERRIER, J., REITMAN, D., ANCONA-BERK, V.A. and CHALMERS, T.C. Meta-analyses of randomized controlled trials. N Engl JMed, 316, 450-455, 1987. 3 ZION, M.M. and BRADLOW, B.A. A controlled pectoris. South AfrMedJ, 35, 11-13, 1961.
clinical trial of “persantin”
@AS) in angina
4 KINSELLA, D., TROUP, W. and MCGREGOR, M. Studies with a new coronary vasodilator Am HeatiJ, 63, 146-151, 1962. drug: Persantin. 5
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